Process for producing solid active substance forms and products thereof

ABSTRACT

A process is described for the production of solid forms of active substances, which forms have good redispersibility in aqueous systems, which comprises mixing PEG and dextran with water and--if phase separation occurs--removing the upper phase, dissolving an active substance in the mixture, where appropriate adding a physiologically tolerated amphiphile, and subsequently removing the water.

The present invention relates to a process for the production of solidforms of active substances, to the products obtained with the aid ofthis process, and to the use of these products for the production ofdrugs.

It is known that phase separation occurs when an aqueous solution ofpolyethylene glycol and a likewise aqueous solution of dextran aremixed. According to U.S. Pat. No. 4,794,000, the lower "colloid-rich"phase can be employed for formulating active substances, whereappropriate after the addition of other auxiliaries such as lecithin.All the formulations described therein are, however, liquid drug forms,often highly viscous, and therefore disadvantageous, especially for oraladministration forms. In addition, there must be expected to be,especially in the liquid state, considerable stability problems of aphysical (phase separation, recrystallization etc.) and chemical nature(hydrolysis reactions, oxidations etc.).

All the auxiliaries employed for the formulation (polyethylene glycol6000, dextran 40 and egg lecithin) display wax-like, sticky propertiesand therefore give rise to problems in the formulation of activesubstances. In their turn, active substances may have a consistencywhich makes pharmaceutical processing difficult.

A very straightforward and efficient process for the production of solidforms of active substances has now been found.

The invention relates to a process for the production of solid forms ofactive substances, which forms have good redispersibility in aqueoussystems, which comprises mixing PEG and dextran with water and--if phaseseparation occurs--removing the upper phase, dissolving an activesubstance in the mixture, where appropriate adding a physiologicallytolerated amphiphile, and subsequently removing the water.

Particularly suitable active substances are those which are soluble inwater. Suitable as PEG (=polyethylene glycol) are, in particular, thosewith a molecular weight of 2,000 to 20,000, e.g. PEG 4,000 and PEG10,000. PEG 6,000 is very particularly suitable.

It is advisable to add an amphiphile to the mixture after adding theactive substance. Suitable as amphiphile are all which arephysiologically tolerated, such as lipids which form bilayer membranes.Examples of these are phospholipids or synthetic amphiphiles. Examplesof synthetic amphiphiles are described in EP-A 331,092. Veryparticularly suitable are phospholipids, preferably lecithins such asegg lecithin, soybean lecithin and synthetic phospholipids.

The removal of the water from the substance mixture is carried out, forexample, by spray-drying or freeze-drying.

The invention also relates to the active substance form which isobtained by the described process and which can be processed in a knownmanner to a finished drug form. The active substance form is verysuitable for the production of instant forms, for example for injectionpreparations and for drinkable solutions, but also, furthermore, inparticular for solid oral drug forms (after the powder has been packedinto hard gelatin capsules or compressed to tablets).

It was surprising that defined mixtures of these sticky, wax-likeauxiliaries yield, even in combination with various active substancesafter removal of the water, a hard, brittle and easily powderedcomposition which is free-flowing and therefore can, for example, bepacked without problems into hard gelatin capsules. These productproperties were not predictable because of the consistency of thestarting materials. It was furthermore surprising that transparent filmsare formed on removal of the water when the solution is, for example,dried in a shallow dish. The films adhere extremely poorly to glass andbecome detached from the substrate without further treatment. Thisproperty was not predictable either, because of the consistency of thestarting materials. The transparency of the films containing activesubstance suggests that the active substance is present in moleculardisperse form, in the form of a quasi "solid solution".

The solid forms of active substances produced as described in thepresent invention can, surprisingly, easily be redispersed in water.

The examples which follow illustrate the invention:

EXAMPLE 1 a) Preparation of the Colloid-Rich Lower Phase

50.0 g of dextran 40 and 15.0 g of polyethylene glycol 6000 were mixedwith 200 ml of distilled water. Stirring was continued at 80° C untilboth substances had completely dissolved. After transfer into aseparating funnel, the mixture was allowed to cool to room temperature,and then the water-clear lower phase was separated off (about 160 ml),the upper phase was discarded.

b) Formulation with Lecithin and Active Substance

20.0 ml of the solution obtained in Example 1 were mixed at 65° C. with0.5 g of verapamil hydrochloride. After the active substance haddissolved, 1.0 g of lecithin E 100 (egg lecithin supplied by Lipoid KG,Ludwigshafen) was dissolved by stirring, likewise at 65° C., until aclear honey-like composition was formed.

c) Drying of the Formulation

Most of the water was removed from the formulation obtained in Example 2in a round-bottom flask on a rotary evaporator (60° C. bath temperature,water pump vacuum). The contents of the flask were subsequently dried ina desiccator over drying agent (P₄ O₁₀) in vacuo for 24 h to completeremoval of the water. The remaining composition was finally powdered ina mortar.

Yield: 6.84 g.

EXAMPLE 2

Preparation was carried out as indicated in Example 1 but with 1.0 g ofverapamil hydrochloride.

Yield: 7.5 g.

EXAMPLE 3

Preparation was carried out as indicated in Example 1 but with 0.5 g ofanipamil hydrochloride.

Yield: 6.75 g.

EXAMPLE 4

Preparation was carried out as indicated in Example 1 but with 1.0 g ofanipamil hydrochloride.

Yield: 7.08 g.

EXAMPLE 5

Preparation was carried out as indicated in Example 1 but with 0.5 g ofgallopamil hydrochloride.

Yield: 7.01 g.

EXAMPLE 6

Preparation was carried out as indicated in Example 1 but with 1.0 g ofgallopamil hydrochloride.

Yield: 7.33 g.

EXAMPLE 7

Preparation was carried out as indicated in Example 1 but with 0.5 g of(S)-emopamil hydrochloride.

Yield: 7.3 g.

EXAMPLE 8

Preparation was carried out as indicated in Example 1 but with 1.0 g of(S)-emopamil hydrochloride.

Yield: 7.6 g.

EXAMPLE 9

Preparation was carried out as indicated in Example 1 but with 2.0 g of(S)-emopamil hydrochloride.

Yield: 8.4 g.

We claim:
 1. A process for the production of solid forms ofwater-soluble active substances of drugs, which forms have goodredispersibility in aqueous systems, which comprises mixing PEG anddextran with water, removing the upper phase from the resultingtwo-phase mixture, dissolving the water-soluble active substance in thewater-clear lower phase which was formed, adding a physiologicallytolerated amphiphile and subsequently removing the water.
 2. A solidform of an active substance, prepared by the process of claim
 1. 3. Adrug composition comprising the active substance of claim 2.